Meptazinol (MEP), (±)-3-(3-ethyl-1-methyl-hexahydro-1H-azepin-3-yl)phenol, formula of which is C15H23NO, has been marketed for the treatment of moderate to severe pain since 1986. Meptazinol was equivalent to some analgesics like pentazocine, dolantin, and dextromethorphan, and less potent than morphine. Unlike other typical opiates, meptazinol causes much less respiratory depression and lower addictive potential. Therefore, it does not fall within the category of narcotic drugs. Meptazinol is useful for many kinds of acute and chronic pains, such as wound, postoperative, obstetrical and cancer pains. It is especially effective and safe for parturition pain because it does not affect the health of infants. For its safety and reliability, meptazinol was embodied in the British Pharmacopoeia in 1998.
Meptazinol hydrochloride was clinically applied as racemate. Racemic meptazinol can be separated into a pair of enantiomers using optically pure tartaric acid and their derivatives. Enantiomer excess (e.e.) of each enantiomer was authenticated >99% by capillary electrophoresis. The absolute configuration of the levo-enantiomer (−)-MEP was determined to be 3S by X-ray diffraction. By mice brain acetylcholinesterase (AChE) inhibition test, (−)-MEP hydrochloride was verified as potent AChE inhibitor, which indicated that levo-enantiomer of MEP and its salts deserved further research and development.
Progressive loss of memory and impairment in cognition are closely related to the deficit of cholinergic function in basal forebrain and hippocampus. Palliative treatments, targeting elevating brain acetylcholine (ACh) levels and recovering cholinergic nerve conduction, alleviate the memory and cognitive deficits. AChE inhibitors increase the synaptic level of ACh by inhibiting the degradation of ACh.
At present, FDA-approved clinical drugs against AD are mainly AChE inhibitors. They are also used to treat other neurodegenerative disorders like PD and other dementias like DLB and VaD, etc.
Routine AChE inhibitors can only relieve the dementia symptoms, but can not prevent the progression of degenerative pathology. In recent years, it is found that two of the AChE active sites, namely the catalytic triad at the bottom and the peripheral anionic sites (PAS) at the entrance, play a key role in inhibition activity. Many highly potent bivalent and bifunctional AChE inhibitors are designed and synthesized, such as bis-tacrine, bis-huperzine B, etc. More recently, dual binding site AChE inhibitors, which simultaneously block the catalytic site and PAS, were indicated to be involved in dual inhibitory action of both AChE and amyloid-β(Aβ) peptide aggregation. They might not only alleviate the cognitive deficit of AD patients, but also act as disease-modifying agents delaying the progression of degenerative pathology. And there is no report about bivalent meptazinol derivatives both at home and abroad.